Dataset Information

Association of the vitamin D metabolism gene CYP24A1 with coronary artery calcification.

ABSTRACT: The vitamin D endocrine system is essential for calcium homeostasis, and low levels of vitamin D metabolites have been associated with cardiovascular disease risk. We hypothesized that DNA sequence variation in genes regulating vitamin D metabolism and signaling pathways might influence variation in coronary artery calcification (CAC).We genotyped single-nucleotide polymorphisms (SNPs) in GC, CYP27B1, CYP24A1, and VDR and tested their association with CAC quantity, as measured by electron beam computed tomography. Initial association studies were carried out in a discovery sample comprising 697 Amish subjects, and SNPs nominally associated with CAC quantity (4 SNPs in CYP24A1, P=0.008 to 0.00003) were then tested for association with CAC quantity in 2 independent cohorts of subjects of white European ancestry (Genetic Epidemiology Network of Arteriopathy study [n=916] and the Penn Coronary Artery Calcification sample [n=2061]). One of the 4 SNPs, rs2762939, was associated with CAC quantity in both the Genetic Epidemiology Network of Arteriopathy (P=0.007) and Penn Coronary Artery Calcification (P=0.01) studies. In all 3 populations, the rs2762939 C allele was associated with lower CAC quantity. Metaanalysis for the association of this SNP with CAC quantity across all 3 studies yielded a P value of 2.9×10(-6).A common SNP in the CYP24A1 gene was associated with CAC quantity in 3 independent populations. This result suggests a role for vitamin D metabolism in the development of CAC quantity.

SUBMITTER: Shen H

PROVIDER: S-EPMC2988112 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Association of the vitamin D metabolism gene CYP24A1 with coronary artery calcification.

Shen Haiqing H Bielak Lawrence F LF Ferguson Jane F JF Streeten Elizabeth A EA Yerges-Armstrong Laura M LM Liu Jie J Post Wendy W O'Connell Jeffery R JR Hixson James E JE Kardia Sharon L R SL Sun Yan V YV Jhun Min A MA Wang Xuexia X Mehta Nehal N NN Li Mingyao M Koller Daniel L DL Hakonarson Hakan H Keating Brendan J BJ Rader Daniel J DJ Shuldiner Alan R AR Peyser Patricia A PA Reilly Muredach P MP Mitchell Braxton D BD

Arteriosclerosis, thrombosis, and vascular biology 20100916 12

<h4>Objective</h4>The vitamin D endocrine system is essential for calcium homeostasis, and low levels of vitamin D metabolites have been associated with cardiovascular disease risk. We hypothesized that DNA sequence variation in genes regulating vitamin D metabolism and signaling pathways might influence variation in coronary artery calcification (CAC).<h4>Methods and results</h4>We genotyped single-nucleotide polymorphisms (SNPs) in GC, CYP27B1, CYP24A1, and VDR and tested their association wit ...[more]

PMID: 20847308

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Project description:Many GWAS have identified novel loci associated with common diseases, but have focused only on main effects of individual genetic variants rather than interactions with environmental factors (GxE). Identification of GxE interactions is particularly important for coronary heart disease (CHD), a major preventable source of morbidity and mortality with strong non-genetic risk factors. Atherosclerosis is the major cause of CHD, and coronary artery calcification (CAC) is directly correlated with quantity of coronary atherosclerotic plaque. In the current study, we tested for genetic variants influencing extent of CAC via interaction with smoking (GxS), by conducting a GxS discovery GWAS in Genetic Epidemiology Network of Arteriopathy (GENOA) sibships (N = 915 European Americans) followed by replication in Framingham Heart Study (FHS) sibships (N = 1025 European Americans). Generalized estimating equations accounted for the correlation within sibships in strata-specific groups of smokers and nonsmokers, as well as GxS interaction. Primary analysis found SNPs that showed suggestive associations (p≤10(-5)) in GENOA GWAS, but these index SNPs did not replicate in FHS. However, secondary analysis was able to replicate candidate gene regions in FHS using other SNPs (+/-250 kb of GENOA index SNP). In smoker and nonsmoker groups, replicated genes included TCF7L2 (p = 6.0×10(-5)) and WWOX (p = 4.5×10(-6)); and TNFRSF8 (p = 7.8×10(-5)), respectively. For GxS interactions, replicated genes included TBC1D4 (p = 6.9×10(-5)) and ADAMTS9 (P = 7.1×10(-5)). Interestingly, these genes are involved in inflammatory pathways mediated by the NF-κB axis. Since smoking is known to induce chronic and systemic inflammation, association of these genes likely reflects roles in CAC development via inflammatory pathways. Furthermore, the NF-κB axis regulates bone remodeling, a key physiological process in CAC development. In conclusion, GxS GWAS has yielded evidence for novel loci that are associated with CAC via interaction with smoking, providing promising new targets for future population-based and functional studies of CAC development.

Dataset Information

Association of the vitamin D metabolism gene CYP24A1 with coronary artery calcification.

Publications

Association of the vitamin D metabolism gene CYP24A1 with coronary artery calcification.

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